FCAS is the least aggressive of the 3 CAPS. Clinical manifestations begin in the first year of life but are often noticeable in the neonatal period. They typically appear within 2 to 7hours of exposure to cold and resolve after approximately 12hours.2 Lesions are not triggered by contact with cold objects.

Muckle-Wells syndrome, also known as urticaria-deafness-amyloidosis syndrome, is similar to FCAS, but it has more severe clinical outcomes. Onset is also common in childhood, but the age of presentation is more variable. Multiple triggers have been described for Muckle-Wells syndrome, the most common of which are heat and cold.

NOMID, or CINCAS, is the severest of the CAPS. The first symptoms tend to appear shortly after birth. Neonatal onset has been reported for 70% of patients and almost 100% of patients show symptoms by the age of 6 months.

Many cases are sporadic and the germline NLRP3 mutation is present only in 55% to 60% of patients, suggesting the existence of considerable genetic heterogeneity with a wide variety of somatic mutations.3,4 Because of this considerable heterogeneity, some authors have suggested that patients with suspected CAPS should undergo initial evaluation before being referred for genetic testing. Proposed criteria include a history of at least 3 recurrent episodes of moderate fever and urticaria, an age of under 20 years of age at disease onset, and elevated CRP levels.4

Cutaneous Manifestations

A characteristic skin manifestation of CINCA/NOMID is a migratory nonpruritic urticaria-like eruption that, unlike in other CAPS, persists for lifetime and has no clear triggers such as cold (Fig. 2). Biopsy shows a superficial and deep perivascular mixed inflammatory infiltrate composed of lymphocytes, neutrophils, and eosinophils together with neutrophilic eccrine hidradenitis5 (Fig. 3).

Figure 2.

NOMID (neonatal-onset multisystem inflammatory disease). Permanent urticaria-like migratory eruption.

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Figure 3.

NOMID (neonatal-onset multisystem inflammatory disease). Mixed perivascular superficial and deep inflammatory infiltrate associated with a neutrophilic infiltrate in the eccrine gland (hematoxylin-eosin, original magnification ×20).

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Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory syndrome. It results from mutations in the MEFV gene, which is located on chromosome 16p13 and encodes the pyrin (or marenostrin) protein. Over 200 MEFV mutations have been reported to date, and the most severe cases of FMF are associated with homozygous M694V mutations. Diagnosis, however, is essentially clinical as not all patients with typical FMF manifestations have a mutation in MEFV. It is therefore likely that other factors are involved in the development of FMF, including, possibly, mutations in other genes.

TNF is an inflammatory cytokine that has a key role in pyrexia, cachexia, production of other cytokines, expression of adhesion molecules, activation of leukocytes, and resistance to cell pathogens. The TNF receptor (TNFR) acts by antagonizing and regulating the actions of circulating TNF. TRAPS is due to a gain-of-function mutation in the TNFR gene that results in dysregulated TNF production. It is an autosomal dominant disorder with mutations in the TNFRSF1A gene, which codes for TNFR1 (also known as p55 or CD120a). The vast majority of TNFRSF1A mutations identified to date are substitution mutations located at exons 2, 3 and 4 of the gene, which codes for the extracellular domains of TNFR1. De novo mutations have also been described in some patients.

HIDS can be divided into 2 entities: classic HIDS, which is associated with the MVK mutation, and variant HIDS, which does not have this mutation or any biochemical evidence of reduced mevalonate kinase activity. Variant HIDS has been linked to low-penetrance mutations in the TNFRSF1A gene and patients often have more latent symptoms. The mutated gene in classic HIDS is the kinase mevalonate gene, located on chromosome 12q24. IgD levels are typically, though not necessarily, elevated. Furthermore, no correlation has been observed between IgD elevation and disease severity or frequency of flares. Considering that IgD levels may be within normal limits in HIDS, they are probably not directly responsible for its clinical manifestations. Their increase is more likely to be a response to an initial autoinflammatory process triggered by trauma, vaccination, stress, or other factors.

PLAID syndrome (PLCG2-associated antibody deficiency and immune dysregulation), also known as familial atypical cold urticaria, is a recently described disorder associated with immunodeficiency, hypogammaglobulinemia, and autoimmune disease caused by deletions in the phospholipase C, gamma-2 (PLCG2) gene. Patients present with urticaria, erythema, burning, and granulomas after exposure to cold and they may also have fever, recurrent sinusitis and lung infections, asthma, and autoimmune disorders. Laboratory studies show increased IgE, decreased circulating IgM, IgG, IgA, and CD19+ B cells, and positive antinuclear antibodies (ANAs).

APLAID syndrome (autoinflammation PLCG2-associated antibody deficiency and immune dysregulation) is similar to PLAID, but is additionally associated with autoinflammatory disorders caused by point mutations in PLCG2. Clinical manifestations include bronchiolitis, recurrent lung infections, cellulitis, arthralgia, enterocolitis, mild immunodeficiency without autoantibodies, and serious eye problems such as corneal erosions, blisters, ulcers, ocular hypertension, and cataracts. Laboratory studies show similar findings to in PLAID, but the ANAs are negative. The PLCC2 mutation in PLAID is a gain-of-function mutation that results in increased signaling. The mutation responsible for APLAID, by contrast, decreases the threshold required for PLCC2 activation. Both syndromes have highly variable cutaneous manifestations, ranging from cold-induced urticaria-like lesions to vesicular-pustular eruptions that worsen with heat and may be seen in both entities. Fixed granulomatous rashes are more common in PLAID, while vesicular-bullous eruptions and recurrent sterile cellulitis plaques are more common in APLAID. In both syndromes, the histopathologic study shows a dense interstitial, perivascular dermal infiltrate composed of neutrophils, lymphocytes, histiocytes, and eosinophils, and leukocytoclastic vasculitis with prominent karyorrhexis. The mutation described for APLAID causes an increase in intracellular calcium, which could activate the NLRP3 inflammasome, generating IL-1 (which would explain why patients partially respond to treatment with anti-IL-1). Depending on the mutational variants present, patients may develop different phenotypic traits, consisting of both cutaneous and systemic manifestations that may or may not be triggered by cold.8,9

Autoinflammatory syndrome associated with lymphedema (AISLE) is due to mutations in the MDFIC gene, which contains the MyoD family inhibitor domain.

NLRP1-associated autoinflammation with arthritis and dyskeratosis (NAIAD) was described by Grandemange. Constitutive activation of NLRP1 leads to increased activation of caspase 1 and a subsequent increase in IL-18 production.

Patients typically present generalized erythematous plaques with superficial pustules, simulating pustular psoriasis, at birth or in the first months of life. There may also be diffuse ichthyosiform scaling that often spares the palms and soles. Mouth ulcers and nail changes in the form of pitting or anonychia are common. Skin biopsy shows subcorneal or spongiform pustules with neutrophils in the epidermis and a dermal neutrophilic infiltrate with variable involvement of the hair follicles, blood vessels, and eccrine glands; immunohistochemical studies show pronounced IL-17 overexpression.10

Flares tend to be accompanied by fever, conjunctivitis, pulmonary infiltrates with respiratory distress, thrombotic episodes, and characteristic bone alterations, such as periostitis, heterotopic ossifications, cervical spinal fusion, and chronic recurrent sterile multifocal osteomyelitis. This last condition, which frequently affects the epiphyses of the long bones, can cause delayed growth. Blood tests show increased acute phase reactants, mild chronic anemia, and neutrophilic leukocytosis without fever. If the autoinflammatory response is severe enough, it can cause multiorgan failure and death.10 Mutations in DIRA have also been linked to preterm delivery as well as intrauterine multiorgan involvement and death.11

Cutaneous lesions in DITRA present as an acute generalized pustular eruption on an erythematous base12 (Fig. 4), similar to that seen in a GPP flare. DITRA lesions are also characterized by recurrent bouts followed by diffuse superficial scaling. In some cases, the lesions can present as psoriasis vulgaris or pustular acral lesions with nail destruction in the form of continuous acrodermatitis. It is possible that many patients who experience GPP flares in the absence of previous manifestations of psoriasis vulgaris could have the DITRA mutation. The frequency of flares varies considerably from one patient to the next, and the lesions may become chronic and acquire the form of erythematous plaques without pustules.12 Histopathologic examination shows the typical features of GPP with parakeratosis, psoriasiform acanthosis, and spongiform pustules, and a predominance of CD8+ T cells, CD3+ T cells, and macrophages.

Figure 4.

DITRA (deficiency of the IL-36 receptor antagonist). Generalized pustular eruption with polycyclic contours on an erythematous base, similar to an outbreak of generalized pustular psoriasis.

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Cutaneous flares have a variable frequency and are associated with high fever, general malaise, and asthenia. Other organs are not affected. Flares generally start in childhood but adult onset has been described. Multiple triggers have been identified and include bacterial and viral infections, menstruation, pregnancy, and drugs, among others. High fever and a poor general state of health are the main distinctive features of DITRA, but involvement in most cases is limited to the skin, unlike in DIRA. Laboratory studies show elevated acute phase reactants and lactate and low levels of albumin, zinc, and calcium.

Cutaneous manifestations of PAPA syndrome typically begin in childhood but worsen considerably at puberty. They consist of severe forms of cystic acne, pathergy, and recurrent sterile ulcers with elevated violaceous borders that are very similar to those seen in pyoderma gangrenosum. An association has also been reported with psoriasis and rosacea.15

Patients with PAPA syndrome may develop fever, although episodes are inconsistent and do not appear to follow any clear pattern. Fever may be accompanied by recurrent episodes of sterile erosive arthritis. This arthritis may be spontaneous or triggered by minor trauma, and although it tends to disappear after puberty, it occasionally persists into adulthood and is severely disabling. Other less common clinical presentations are recurrent otitis, pharyngeal papillomatosis, lymphadenopathy, splenomegaly, thrombocytopenia, hypergammaglobulinemia, hemolytic anemia, and sulfonamide-induced pancytopenia.

Skin lesions are not a characteristic finding in Majeed syndrome. Pustular involvement is more common and there have also been reports of dermatoses similar to those seen in Sweet syndrome and psoriasis.

Osteomyelitis flare-ups are invariably accompanied by high fever, pain, and swelling of the large joints. Foci of osteomyelitis are more common in the clavicles, sternum, and the long bones, and less common in the vertebral bodies and jaw. This chronic inflammation causes delayed growth, low stature, and flexion contractures, and radiographic images show osteolytic lesions and areas of sclerosis.

Characteristic cutaneous manifestations are multiple facial pustules and pyoderma gangrenosum–like lesions.17

The skin lesions tend to be accompanied by fever, arthromyalgia, and myositis, and increased acute phase reactants.

Patients typically develop small numbers of small aphthous lip or mouth ulcers that heal without scarring, in addition to nonspecific generalized urticaria-like erythema of varying intensity in a small proportion of patients.

Acute recurrent pharyngitis and tonsillitis with negative cultures and enlarged cervical lymph nodes are common. There may also be accompanying constitutional symptoms, such as abdominal pain, headache, arthralgia, cough, nausea, and diarrhea. As with other periodic fever syndromes, blood tests may show elevated acute phase reactants during flares.

Severe oral ulcers that result in deforming scarring and microstomia are the main cutaneous manifestation in PFIT.

Additional clinical features include mouth ulcers, failure to thrive, recurrent infections, and thrombocytopenia.

The clinical manifestations are very similar to those observed in childhood-onset Behçet disease, with oral and genital ulcers.

Patients also frequently develop fever, general malaise, eye inflammation, and early-onset arthralgia and arthritis.

The clinical manifestations are heterogeneous and consist of erythema nodosum lesions, pustules, necrotizing ulcers, superficial thrombophlebitis and vasculitis, and lesions similar to those seen in pyoderma gangrenosum or Sweet syndrome, among others. It is associated with positive pathergy reactions. Recurrent mouth ulcers are the first manifestation in a high percentage of patients. They tend to be multiple, painful, and heal without leaving a scar, unlike genital ulcers, which leave characteristic flat scars. Neutrophilic vasculitis and/or thrombosis are characteristic histopathologic findings.

Eye involvement is the main cause of morbidity in Behçet syndrome. The most common condition is posterior uveitis, but anterior uveitis and uveitis with hypopyon are also observed. Patients may also develop arthritis and a large spectrum of manifestations secondary to systemic vasculitis, such as arterial and venous thrombosis, aneurysms, and digestive and neurological symptoms.